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Alzheimer’s disease is a devastating condition that develops due to extensive neuronal damage leading to aberrant neural network activity. A common factor in Alzheimer’s and many other neurodegenerative diseases is the dysfunction of mitochondria. These energy-producing metabolic hubs also influence signalling cascades, ROS production and redox control. Mitochondria are trafficked along the cytoskeleton, vital for long-lived neurons. Delivery and maintenance of functional mitochondria to energy-consuming synapses is critical for correct neuronal function and protection against cell death.

Mitochondria efficiently buffer calcium, maintaining appropriate physiological calcium signals and protecting from pathological calcium overload. Fascinatingly, mitochondrial transport proteins disengage in high calcium, delivering the organelles where most needed. Mitochondria are also susceptible to damage which can cause a cascade of spreading calcium overload that disrupts ATP production, increases ROS and induces apoptosis.

This project builds on exciting new findings that show that mitochondrial transport is disrupted by exposure to either the Alzheimer’s-associated amyloid, or diabetic-like hyperglycaemia. The project will therefore examine whether the combination of a high-glucose and high-amyloid environment may exacerbate mitochondrial alterations and lead to disrupted neuronal function. We will investigate how each hyperglycaemia, amyloid and their combination affects neuronal function; as well as the potential that pharmacological or endogenous mitochondrially-targeted agents could protect again neuronal dysfunction.